Pain relief implant pellet and method using same

ABSTRACT

An emplantable pellet comprising one or more pain relief agents. A method to relief pain at the injection site of one or more implanted pharmaceutical pellets comprising the step of implanting one or more of Applicant&#39;s implantable pellets. A method to adjust the in vivo rate of release of one or more pain relief agents from Applicants&#39; implantable pellets. A method to adjust the rate of systemic delivery of one or more pharmaceutical agents implanted adjacent one or more of Applicants&#39; implantable pellets.

FIELD OF THE INVENTION

[0001] The present invention is broadly concerned with a pain reliefcomposition in implantable pellet form, and a method to relieve painusing such implantable pellets.

BACKGROUND OF THE INVENTION

[0002] Animal well-being and treatment are major concerns for animalwelfare groups and animal agriculturalists. Animal well-being andtreatment are continual concerns because stressed or uncomfortableanimals do not efficiently and profitably produce milk, meat, or eggs.

[0003] Implant technology, that is to say, procedures involvingsubcutaneous implant of pharmaceuticals and medical devices, is now wellaccepted and widespread in the areas of animal health and productionenhancement as well as human health. Growth stimulants are commonly usedto enhance the body weight of animals which are raised for harvesting,such as cattle, swine, sheep, turkeys, chickens, and the like.

[0004] In the case of cattle and sheep, approved growth stimulants areadministered as solid pellets which are injected by an implanterequipped with a hypodermic needle. The needle is used to make a surfaceself-sealing and, non-coring implant receiving puncture beneath the skinof the ear of the animal. Small pellets of growth-promoting hormones areforced through the needle and left under the skin as the needle isremoved from the ear. The ears are commonly discarded in harvesting,such that no unabsorbed residues of such pellets will end up in foodproducts intended for humans or domestic animals. The pharmaceutical inthe pellets is normally formulated for timed release and continuous,sustained absorption of the active ingredients over an extended periodof time.

[0005] Many types of pharmaceuticals such as bioactive compounds mayalso be implanted and include insulin, endocrine hormones for control ofreproduction, vaccines, and biocides for flea and parasite control inhumans, horses, and domestic animals such as dogs and cats. Thecompounds may be administered subcutaneously at any suitable location onthe body. Included as such a pharmaceutical are synthetic derivatives ofnaturally occurring compounds such as trenbolone acetate, a syntheticderivative of testosterone currently used in cattle growth-promotingimplants. As those skilled in the art will appreciate, similartherapeutic procedures may be employed to implant drug delivery devicessuch as controlled release osmotic pumps in humans and animals as wellas transponder devices in animals.

[0006] In the case of food-producing animals, the pellets are normallyimplanted while an animal is confined in a chute. An ear is grasped inone hand, and an implanter device having a large hypodermic needle isused to puncture the hide and subcutaneously inject a pellet dose intoan implant-receiving puncture. The implanting must be done carefully toinsure that the pellets are properly placed and that no pellet remainsextending from the puncture outside the hide. The procedure must becarried out quickly since the animals are not entirely cooperative andmay shake their heads to free the held ear.

[0007] In addition to implanting pharmaceutical pellets, is it alsoknown in the art to implant certain anti-inflammatory agents. As thoseskilled in the art will appreciate, when tissue injury occurs, whethercaused by bacteria, trauma, chemicals, heat, or any Is other phenomenon,the body's inflammatory response is stimulated. In response to signalsreleased from the damaged cells (e.g., cytokines), extravascularizationof immune effector cells is induced. Under ordinary circumstances theseinvading immune effector cells kill the infectious agent and/or infectedor damaged cells (through the release of killing substances such assuperoxides, performs, and other antimicrobial agents stored ingranules), remove the dead tissues and organisms (through phagocytosis),release various biological response modifiers that promote rapid healingand covering of the wound (quite often resulting in the formation offibrotic scar tissue), and then, after the area is successfully healed,exit from the site of the initial insult.

[0008] Once the site is perceived to be normal, the local release ofinflammatory cytokines ceases and the display of adhesion molecules onthe vessel endothelium returns to basal levels. In some cases, however,the zeal of these interacting signals and cellular systems, which aredesigned to capture and contain very rapidly multiplying infectiousagents, act to the detriment of the body, killing additional, otherwisehealthy, surrounding tissue. This additional unnecessary tissue deathfurther compromises organ function and sometimes results in death of theindividual.

[0009] The present invention provides a pain relief pellet system whichdelivers localized, controlled and sustained release of a predeterminedquantity of one or more pain relief agents, in optional combination withone or more anti-inflammatory agents, one or more polymeric excipients,and/or one or more surfactants. Applicants' anesthetic/analgesic pelletsystem can be used in combination with one or more pharmaceuticalimplants as part of a single procedure in order to provide desiredpharmaceutical to the animal while simultaneously alleviating pain and,optionally, inflammation at the injection site.

SUMMARY OF THE INVENTION

[0010] The present invention includes an implantable pain relief pellet.Applicants' invention further includes a method for implantation ofsame. In certain embodiments, Applicants' method also includesimplantation of one or more pharmaceutical pellet, thereby providinglocalized, sustained, anesthetic/analgesic release at an injection sitein order to reduce pain around the site of the injection.

[0011] In certain embodiments, Applicants' method also includesimplantation of one or more anti-inflammatory pellets, thereby providinglocalized, sustained, anti-inflammatory release at an injection site inorder to reduce inflammation around the site of the injection.Applicants' invention further comprises a pellet system which includesan implanter apparatus for subcutaneously injecting pharmaceuticalpellets into an animal through the bore of a hypodermic needle which isremotely coupled to a pellet magazine, and simultaneously implanting oneor more anesthetic/analgesic/anti-inflammatory pellet into the injectionsite. Applicants' invention further includes a method comprisingimplantation of predetermined doses of one or more pharmaceutical orcombination and an anesthetic/analgesic/anti-inflammatory agent(s) in asingle injection.

[0012] Applicants' invention further comprises a method which permits anoperator to selectively implant an anesthetic/analgesic dose into ananimal, including humans. Applicants' invention further comprises amethod which permits serial injection of large numbers of animals in asingle session.

BRIEF DESCRIPTION OF THE DRAWINGS

[0013] The invention will be better understood from a reading of thefollowing detailed description taken in conjunction with the drawings inwhich like reference designators are used to designate like elements,and in which:

[0014]FIG. 1 is a fragmentary perspective view of an implantationapparatus of use when employing Applicants' method to relieve pain;

[0015]FIG. 2 is a fragmentary cross-sectional view showing Applicants'implantable pain relief pellets disposed within the implantationapparatus;

[0016]FIG. 3 is a fragmentary cross-sectional view showing implantationof Applicants' pain relief pellets;

[0017]FIG. 4 recites Applicants' formulations A through S, wherein thoseformulations comprise one or more anesthetic agents in combination withone or more analgesic agents;

[0018]FIG. 5A recites Applicants' formulations AA through AS whichinclude one or more anesthetic agents in combination with one or moreadditional ingredients;

[0019]FIG. 5B recites Applicants' formulations AT through BL whichinclude one or more anesthetic agents in combination with one or moreadditional ingredients;

[0020]FIG. 6A recites Applicants' formulations CA through CS whichinclude one or more analgesic agents in combination with one or moreadditional ingredients;

[0021]FIG. 6B recites Applicants' formulations CT through DL whichinclude one or more analgesic agents in combination with one or moreadditional ingredients;

[0022]FIG. 7A recites Applicants' formulations EA through ES whichinclude one or more anesthetic agents in combination with one or moreanalgesic agents in combination with one or more additional ingredients;and

[0023]FIG. 7B recites Applicants' formulations ET through FL whichinclude one or more anesthetic agents in combination with one or moreanalgesic agents in combination with one or more additional ingredients.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0024] It is to be understood that the disclosed embodiments are merelyexemplary of the invention, which may be embodied in various forms.Therefore, specific structural, composition, and/or functional detailsdisclosed herein are not to be interpreted as limiting, but merely as abasis for the claims and as a representative basis for teaching oneskilled in the art to variously employ the present invention invirtually any appropriately detailed structure, composition, and/ormethod.

[0025] Applicants' invention comprises an implantable pellet comprisingone or more pain relief agents. By pain relief agent, Applicants meanone or more anesthetic agents and/or one or more analgesic agents. Byanesthetic agent, Applicants mean a composition that induces a partialor total loss of the sense of pain, temperature, touch, and the like. Byanalgesic agent, Applicants mean a composition that induces a state ofnot being able to feel pain. Applicants' pain relief pellet can beformed by various methods including, but not limited to, compressionmolding and/or encapsulation.

[0026] In certain embodiments, Applicants' pain relief pellets compriseone or more anesthetic agents, including those used in caudal, epidural,inhalation, injectable, retrobulbar, and spinal applications, such asbupivacaine, lidocaine, prilocaine, and mixtures thereof. In theseembodiments, the one or more anesthetic agents are present in an amountbetween about 5 weight percent and about 95 weight percent. FIGS. 5A and5B recite Applicants' formulations AA through BL which include one ormore anesthetic agents in combination with one or more additionalingredients discussed below.

[0027] In alternative embodiments, Applicants' pain relief pelletscomprise one or more analgesic agents, such as acetaminophen, ibuprofen,fluriprofen, ketoprofen, voltaren, phencetin, salicylamide, and mixturesthereof. In these embodiments, the one or more analgesic agents arepresent in an amount between about 5 weight percent and about 95 weightpercent. FIGS. 6A and 6B recite Applicants' formulations CA through DLwhich include one or more analgesic agents in combination with one ormore additional ingredients discussed below.

[0028] In yet other embodiments, Applicants' pain relief pelletscomprise one or more anesthetic agents in combination with one or moreanalgesic agents. In these embodiments, the one or more anestheticagents in combination with the one or more analgesic agents are presentin an aggregate amount between about 5 weight percent and about 95weight percent. FIG. 4 recites Applicants' formulations A through S,wherein those formulations comprise one or more anesthetic agents incombination with one or more analgesic agents.

[0029] The weight percentages recited in FIG. 4 represent only theanesthetic/analgesic component of Applicants' pain relief formulation.In contrast, each formulation recited in FIGS. 7A and 7B includes one ofthe formulations recited in FIG. 4 in combination with one or moreadditional ingredients discussed below. For example, formulation EA(FIG. 7A) comprises an anesthetic agent(s)/analgesic agent(s) componentpresent at about 95 weight percent in combination with a surfactantcomponent present at about 5 weight percent. The anestheticagent(s)/analgesic agent(s) component of formulation EA includes any ofthe formulations recited in FIG. 4. Thus, formulation EA includes atabout a 95 weight percentage level, one or more of compositions AAthrough AS.

[0030] In certain embodiments, Applicants' implantable pellet alsocomprises one or more anti-inflammatory agents. By anti-inflammatoryagent, Applicants mean a composition that minimizes injury-producedvascular dilatation and the greatly increased blood flow associatedtherewith, and/or exudation of fluid from blood vessels into tissueswith concomitant swelling, and/or migration of leukocytes into thetissues, and/or gelation of fibrogen in intercellular spaces.

[0031] In certain embodiments, the one or more anti-inflammatory agentsare selected from the group comprising, but not limited to,corticosteriods, keratolytics, and mixtures thereof. The one or moreanti-inflammatory agent components of Applicants' composition arepresent in an amount up to about 90 weight percent.

[0032] Applicants' composition is formulated so as to be biodegradablein the target animals, including humans, and to control release of theactive ingredients. In certain embodiments, Applicants' anestheticcomposition includes one or more excipients, including but not limitedto, polyethylene glycol, starch, dextran, polyvinylalcohol, poly2-ethyl-2-oxazoline, and mixtures thereof. In certain embodiments, suchexcipients are present in an amount at up to about 50 weight percent. Inother embodiments, such excipients are present in an amount betweenabout 5 weight percent and about 25 weight percent. In alternativeembodiments, such excipients are present in an amount between about 10weight percent and about 20 weight percent.

[0033] Poly-2-ethyl-2-oxazoline is a water-soluble polymeric material.As those skilled in the art will appreciate, poly 2-ethyl-2-oxazolinecomprises substituted polyethyleneimine II. Polymer II can be formed bya ring-opening polymerization of 2-ethyloxazoline I.

[0034] In certain embodiments, Applicants' implantable compositionincludes polymer II having a number average molecular weight of about5,000, i.e. n equals about 50. This polymeric material is sold incommerce under the name AQUAZOL® 5 by Polymer Chemistry Innovations,Inc., 4231 South Fremont, Tucson, Ariz. 85714. In other embodiments,Applicants' implantable composition includes polymer II having a numberaverage molecular weight of about 50,000, i.e. n equals about 500. Thispolymeric material is sold in commerce under the name AQUAZOL® 50 byPolymer Chemistry Innovations, Inc. In alternative embodiments,Applicants' implantable composition includes polymer II having a numberaverage molecular weight of about 500,000, i.e. n equals about 5000.This polymeric material is sold in commerce under the name AQUAZOL® 500by Polymer Chemistry Innovations, Inc.

[0035] In certain embodiments, Applicants' pain relief pellets compriseone or more surfactants. Such surfactants are selected from the groupconsisting of anionic surfactants, amphoteric surfactants, non-ionicsurfactants, and mixtures thereof. Certain embodiments of Applicants'pain relief pellet include one or more nonionic surfactants having aHydrophilic Lipophilic Balance (“HLB”) between about 5 and about 20.Such nonionic surfactants include polyoxyethylene/polyoxypropylene blockco-polymers, polyoxyethylene/alkyl ethers, polyoxyethylene sorbitanesters, and mixtures thereof. In certain embodiments, the surfactantcomponent of Applicants' implantable composition is present in an amountup to about 20 weight percent. In other embodiments, such one or moresurfactants are present in an amount between about 1 weight percent andabout 10 weight percent. In alternative embodiments, such one or moresurfactants are present in an amount between about 3 weight percent andabout 5 weight percent.

[0036] The rate of in vivo release from an implanted pellet comprisingone or more anesthetic agents, and/or one or more analgesic agents,and/or one or more anti-inflammatory agents, can be adjusted by: (i)varying the weight percentage of one or more water soluble polymericexcipients, such as poly 2-ethyl-2-oxazoline, and/or (ii) including afirst surfactant and varying the weight percentage of that firstsurfactant, (iii) including a first surfactant at a first weightpercentage level and a second surfactant at a second weight percentagelevel, and varying the ratio between said first weight percentage leveland said second weight percentage level, and/or (iv) including one ormore non-ionic surfactant(s) and varying the HLB(s) of those one or morenon-ionic surfactants. Thus, the inclusion of a water-soluble, polymericexcipient in combination with one or more surfactant allows theformulator to adjust the rate of time release of the anaestheticagents/analgesic agents/anti-inflammatory agents comprising Applicants'implantable pellets. In addition, the rate of systemic delivery of oneor more pharmaceutical agents released from a pharmaceutical pelletimplanted in an animal and disposed adjacent one or more of Applicants'implantable pellets can be adjusted by: (i) including a first surfactantand varying the weight percentage of that first surfactant, (ii)including a first surfactant at a first weight percentage level and asecond surfactant at a second weight percentage level, and varying theratio between said first weight percentage level and said second weightpercentage level, and/or (iii) including one or more non-ionicsurfactant(s) and varying the HLB(s) of those one or more non-ionicsurfactants.

[0037] In certain embodiments, Applicants' pain relief pellet includesone or more lubricants, including, for example, magnesium stearateand/or croscarnellose sodium, especially as sold under the trademarkAc-Di-Sol® by FMC. Such lubricants are present in an amount up to about5.0 weight percent. Applicants' anesthetic composition may optionallyalso include a wide range of additives to facilitate application, tocontrol release, to stabilize the composition and for other reasons wellknown in the art.

[0038] In certain embodiments, Applicants' method utilizes an implanterhaving a pellet magazine in combination with an injection needle, aswell as structure permitting injection of pellets from the magazinethrough the needle for implantation under the skin of an animal. Incertain embodiments of Applicants' method, the magazine is loaded withpain relief pellets and pharmaceutical pellets for distribution insequence singly. In alternative embodiments, the magazine is loaded withpain relief pellets and pharmaceutical pellets for distribution inmultiples into the same injection site.

[0039] Broadly speaking, the pellet system used in Applicants' methodincludes an implanter apparatus for subcutaneously implantingpharmaceutical pellets in an animal through the bore of a hypodermicneedle which is remotely coupled to a pellet magazine, and a pluralityof pellets sized to be implanted through the needle and positioned inthe magazine for selective alignment of a pellet with the needle. In oneembodiment, the pellets include one or more pharmaceutical doses, and atleast one pain relief pellet. In certain embodiments, that pain reliefpellet includes one or more anti-inflammatory agents. These variouspellets are arranged in the magazine in sequential order forsimultaneous delivery of a pharmaceutical dose and ananesthetic/analgesic/anti-inflammatory dose as part of a singleinjection.

[0040] Referring to FIG. 1, general the reference numeral 10 representsa pellet implantation system in accordance with the invention. Theimplantation system 10 broadly includes a slide action implanterapparatus 12 which is used to implant solid form drugs orpharmaceuticals, such as pain relief pellets 40 (FIG. 2) andpharmaceutical pellets 42 (FIG. 2) from a magazine strip 16 into ananimal 30 through a hypodermic needle 18. The needle 18 is utilized byan operator 26 to create an opening 44 that produces an implantreceiving puncture 44 (FIG. 2) in the animal 30.

[0041] A suitable implanter apparatus 12 is illustrated and described indetail in U.S. Pat. No. 5,522,797, which is hereby incorporated herein,and generally includes a housing 20 having a grip 22 with a triggerassembly 24 pivotally mounted therein. An impeller 17 is slidablymounted within the housing 20 in alignment with an interior bore 46(FIG. 2) of the needle 18 and aligned chambers 16 of the loaded pelletmagazine strip 14. The needle 18 is used to puncture through the skin orhide 32 of an animal's ear 34, and the trigger 24 is squeezed toward thegrip 22 of the housing 20 to initiate injection of the pellets 40 and 42and so as to cause the impeller 17 to be urged through the magazinechamber 16 and needle bore 46, thereby forcing the pellets 40 and 42through the bore 46 of needle 18 and into the puncture 44 in the ear 34.

[0042] Each magazine strip 14 of the implanter 12 typically containsmultiple parallel aligned pellet doses stored in corresponding pelletchambers 16, which are connected by interconnecting webs 28. Thechambers 16 are slightly conical in shape and are arranged in aside-by-side parallel relation. The chambers 16 may have internalfrictional formations such as beads or posts (not shown) to retain thepellets 40 and 42 therein prior to insertion and which can be easilybypassed by application of pressure to the trigger 24. A plurality ofstrips 14 can be connected in end-to-end relation to increase theimplanting capacity before the implanter 12 requires reloading. As thepellets 40 and 42 in an individual magazine strip 14 are exhausted theempty strip 14 can be detached from the remaining strips 14 located inthe implanter 12 and discarded.

[0043] Each pellet chamber 16 is loaded with an arrangement of pellets40 and 42. The pellets 40 and 42 are composed of one or more activeingredients, either alone, formed into a pellet, in conjunction with oneor more excipients, formed as part of a polymeric based release systemsuch as co-extruded polymers or matrix polymer systems, or included aspart of a delivery system based on mass transfer through an opening or agel matrix, either by diffusion or osmotic pressure pumping of theactive ingredient.

[0044] Pellets 42 are formulated to include pharmaceuticals such asantibiotics, insulin, endocrine hormones (such as growth and birthcontrol hormones), vaccines, parasiticides or other biocides. Thus incertain embodiments, one pellet 40 contains an anesthetic/analgesiccomposition/anti-inflammatory composition, and the other pellet 42contains one or more pharmaceutical agents. It is foreseen that thenumber of pellets for each group may vary or that the pain reliefagent(s) and other non-pain relief pharmaceuticals may be mixed in oneor more of the pellets 40.

[0045] Each magazine chamber 16 is prefilled with a preferred number ofdiscrete pellets 42, each containing a dose of one or morepharmaceuticals such as trenbolone acetate bovine growth hormone, alongwith at least one pellet 40 containing ananesthetic/analgesic/anti-inflammatory composition. The magazine strip14 is preferably loaded onto implanter housing 20 in an orientation sothat the pharmaceutical pellet 42 will be delivered first, followed bythe anesthetic pellet 40.

[0046] In use, an operator grasps the implanter 12 by the grip 22 andurges the needle 18 into the hide 32 and under the skin of the targetanimal 30 to make the implant-receiving puncture 44. The puncture 44shown in FIG. 2 is incomplete and the depth of the implant receivingpuncture 44 shown in FIG. 2 is about half of the total depth as shown inFIG. 3. The operator 26 depresses the trigger member 24, therebypropelling a pin 50 (FIG. 3) of the impeller member 17 forwardly throughan aligned magazine chamber 16, forcing the pellets 40 and 42 throughthe needle bore 46 and into the implant receiving puncture 44. Theoperator 26 then withdraws the needle 18, leaving the pellets 40 and 42in the implant-receiving puncture 44.

[0047] While the pharmaceuticals in pellet 42 are absorbed and utilizedsystemically by the animal 30, in one embodiment pellet 40 preferablydelivers most of its dose at the site of the implant receiving puncture44, although some of the anesthetic/analgesic/anti-inflammatory agent(s)may be absorbed and carried systemically. In this embodiment, pellet 40is preferably specifically formulated to deliver its dose locally ratherthan systemically, and at a controlled, predetermined rate over apreselected period of time. In another embodiment, pellet 40 isformulated to deliver a systemic anesthetic/analgesic/anti-inflammatorydose.

[0048] Those skilled in the art will appreciate that the magazine strip14 may be loaded for selective injection of more than one pain reliefpellet 40. Where a number of pellets 42 of pharmaceutical are to bedelivered, the pharmaceutical may be sandwiched between two or more painrelief pellets to provide localized anesthetic release at both ends of along implant receiving puncture 44. It is foreseen that in otherembodiments pain relief pellets may be alternated in a stack of pelletsof other pharmaceuticals, for delivery throughout the implant-receivingpuncture 44.

[0049] Applicants' implantable pain relief pellets, and method torelieve pain using same, may be employed efficaciously with cows,horses, sheep, swine, dogs, cats or any other suitable animal, includinghumans.

[0050] While the invention has been described in detail herein inaccordance with certain preferred embodiments thereof, manymodifications and changes therein my be effected by those skilled in theart. Accordingly, it is intended by the appended claims to cover allsuch modifications and changes as fall within the true spirit and scopeof the invention.

We claim:
 1. An implantable pellet, comprising one or more pain reliefagents.
 2. The implantable pellet of claim 1, wherein said implantablepellet is formed by compression molding said one or more pain reliefagents.
 3. The implantable pellet of claim 1, wherein said one or morepain relief agents comprise one or more anesthetic agents.
 4. Theimplantable pellet of claim 1, wherein said one or more pain reliefagents comprise one or more analgesic agents.
 5. The implantable pelletof claim 1, wherein said one or more pain relief agents comprises one ormore anesthetic agents and one or more analgesic agents.
 6. Theimplantable pellet of claim 1, further comprising one or moresurfactants.
 7. The implantable pellet of claim 6, wherein said one ormore surfactants comprise one or more non-ionic surfactants having anHLB between about 5 and about
 20. 8. The implantable pellet of claim 1,further comprising one or more excipients, wherein said one or moreexcipients are present in an amount up to about 50 weight percent. 9.The implantable pain relief pellet of claim 8, wherein said one or moreexcipients comprise poly-2-ethyl-2-oxazoline.
 10. The implantable painrelief pellet of claim 1, further comprising one or moreanti-inflammatory agents.
 11. The implantable pain relief pellet ofclaim 10, wherein said one or more anti-inflammatory agents is presentin an amount up to about 90 weight percent.
 12. An implantable pellet,comprising: one or more anesthetic agents; one or more analgesic agents;one or more anti-inflammatory agents; one or more surfactants; and oneor more excipients.
 13. A method to reduce pain at the site of asubdermal implantation of one or more pharmaceutical pellets, comprisingthe steps of: implanting in an animal one or more pharmaceuticalpellets, wherein each of said one or more pharmaceutical pelletscomprises one or more pharmaceutical agents; and implanting in saidanimal one or more pain relief pellets, wherein at least one of said oneor more pain relief pellets is disposed adjacent at least one of saidone or more pharmaceutical pellets.
 14. The method of claim 13, whereineach of said one or more pain relief pellets comprises one or more painrelief agents.
 15. The method of claim 14, wherein said one or more painrelief agents comprise one or more anesthetic agents.
 16. The method ofclaim 14, wherein said one or more pain relief agents comprise one ormore analgesic agents.
 17. The method of claim 14, wherein said one ormore pain relief agents comprises one or more anesthetic agents and oneor more analgesic agents.
 18. The method of claim 14, wherein each ofsaid one or more pain relief pellets further comprises one or moresurfactants.
 19. The method of claim 18, wherein said one or moresurfactants comprise one or more non-ionic surfactants.
 20. The methodof claim 14, wherein said one or more pain relief pellets furthercomprise one or more excipients.
 21. The method of claim 20, whereinsaid one or more excipients comprise poly-2-ethyl-2-oxazoline.
 22. Themethod of claim 14, wherein said one or more pain relief pellets furthercomprise one or more anti-inflammatory agents.
 23. The method of claim13, wherein said one or more pain relief pellets comprise: one or moreanesthetic agents; one or more analgesic agents; one or moreanti-inflammatory agents; one or more surfactants; and one or moreexcipients.
 24. The method of claim 13, further comprising the steps of:providing an implantation apparatus for subdermally disposing in ananimal one or more pellets; disposing in said implantation apparatus oneor more pharmaceutical pellets; disposing in said implantation apparatusone or more pain relief pellets; inserting said implantation apparatusthrough the skin of said animal; disposing in said animal said one ormore pharmaceutical pellets; disposing in said animal said one or morepain relief pellets; and removing said implantation apparatus from saidanimal.
 25. A method to adjust the in vivo rate of release of one ormore pain relief agents from an implanted pellet, comprising the stepsof: providing one or more implantable pellets comprising one or morepain relief agents in combination with a first surfactant, wherein saidfirst surfactant is present at a first weight percentage; adjusting saidfirst weight percentage; and implanting in an animal said one or moreimplantable pellets.
 26. The method of claim 25, wherein said one ormore implantable pellets further comprise a second surfactant, whereinsaid second surfactant is present at a second weight percentage, furthercomprising the step of adjusting said second weight percentage.
 27. Themethod of claim 26, wherein said first surfactant comprises a firstnon-ionic surfactant having a first HLB and said second surfactantcomprises a second non-ionic surfactant having a second HLB.
 28. Themethod of claim 26, further comprising the step of adjusting the ratiobetween said first weight percentage and said second weight percentage.29. The method of claim 28, wherein said first surfactant comprises afirst non-ionic surfactant having a first HLB and said second surfactantcomprises a second non-ionic surfactant having a second HLB.
 30. Themethod of claim 25, wherein said implantable pellet further comprises awater soluble polymer, wherein said water soluble polymer is present ata third weight percentage, further comprising adjusting said thirdweight percentage.
 31. A method to adjust the systemic delivery of oneor more pharmaceutical agents released from one or more implantedpellet, comprising the steps of: providing one or more first implantablepellets comprising one or more pharmaceutical agents; providing one ormore second implantable pellets comprising one or more pain reliefagents in combination with a first surfactant, wherein said firstsurfactant is present at a first weight percentage; adjusting said firstweight percentage; implanting one or more of said first pellets in ananimal; and implanting in said animal one or more of said secondpellets, wherein at least one of said one or more second pellets isdisposed adjacent at least one of said one or more first pellets. 32.The method of claim 31, wherein said one or more second pellets furthercomprise a second surfactant, wherein said second surfactant is presentat a second weight percentage, further comprising the step of adjustingsaid second weight percentage.
 33. The method of claim 32, wherein saidfirst surfactant comprises a first non-ionic surfactant having a firstHLB and said second surfactant comprises a second non-ionic surfactanthaving a second HLB.
 34. The method of claim 32, further comprising thestep of adjusting the ratio between said first weight percentage andsaid second weight percentage.
 35. The method of claim 34, wherein saidfirst surfactant comprises a first non-ionic surfactant having a firstHLB and said second surfactant comprises a second non-ionic surfactanthaving a second HLB.
 36. The method of claim 25, wherein said one ormore second implantable pellets further comprise a water solublepolymer, wherein said water soluble polymer is present at a third weightpercentage, further comprising the step of adjusting said third weightpercentage.